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Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-ß Type I Receptor Kinase In vivo

Authors' Affiliations: Departments of ¹ Internal Medicine and ² Surgery, The Cancer Institute of New Jersey, and ³ Department of Pathology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey; ⁴ Department of Genetics, Rutgers University, Piscataway, New Jersey; and ⁵ Scios, Inc., Fremont, California

Requests for reprints: Michael Reiss, Division of Medical Oncology, Department of Internal Medicine, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Room 2007, 195 Little Albany Street, New Brunswick, NJ 08903. Phone: 732-235-6031; Fax: 815-333-3972; E-mail: michael.reiss{at}umdnj.edu.

Purpose: Transforming growth factor-ß (TGF-ß) suppresses tumor development by inhibiting cellular proliferation, inducing differentiation and apoptosis, and maintaining genomic integrity. However, once tumor cells escape from the tumor-suppressive effects of TGF-ß, they often constitutively overexpress and activate TGF-ß, which may promote tumor progression by enhancing invasion, metastasis, and angiogenesis and by suppressing antitumor immunity. The purpose of this study was to test this hypothesis using TGF-ß pathway antagonists.

Experimental Design: We examined the effects of selective TGF-ß type I receptor kinase inhibitors, SD-093 and SD-208, on two murine mammary carcinoma cell lines (R3T and 4T1) in vitro and in vivo.

Results: Both agents blocked TGF-ß-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, in a dose-dependent manner, with IC₅₀ between 20 and 80 nmol/L. TGF-ß failed to inhibit growth of these cell lines but stimulated epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro. These effects were inhibited by SD-093, indicating that these processes are partly driven by TGF-ß. Treatment of syngeneic R3T or 4T1 tumor-bearing mice with orally given SD-208 inhibited primary tumor growth as well as the number and size of metastases. In contrast, SD-208 failed to inhibit R3T tumor growth or metastasis in athymic nude mice. Moreover, in vitro anti-4T1 cell cytotoxic T-cell responses of splenocytes from drug-treated animals were enhanced compared with cells from control animals. In addition, SD-208 treatment resulted in a decrease in tumor angiogenesis.

Conclusion: TGF-ß type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast cancer.

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